Biocompatible polyanhydrides having improved degradation properties and processability with useful degradation products have now been developed. In one embodiment, the polyanhydrides are ortho-substituted aromatic polyanhydrides produced from ortho-substituted bis-aromatic carboxylic acid anhydrides which degrade into biologically active materials such as salicylates. In another embodiment, the polyanhydrides are aliphatic in structure and degrade into alpha-hydroxy acids. Salicylates are used routinely as anti-inflammatory, antipyretic, analgesic, and anti-oxidant agents, while alpha-hydroxy acids are incorporated into many skin moisturizers, cleansers, lotions, creams shampoos, tanning products and lipsticks to promote smoother, clearer skin with fewer wrinkles. Thus, the biocompatible polyanhydrides of the present invention can be administered to a host via a variety of routes including, but not limited to orally, subcutaneously, intramuscularly, intradermally and topically, depending upon the degradation product of the polyanhydride and the selected use for the degradation product.
Polymers comprising aromatic or aliphatic anhydrides have been studied extensively over the years for a variety of uses. For example, in the 1930s fibers comprising aliphatic polyanhydrides were prepared for use in the textile industry. In the mid 1950s, aromatic polyanhydrides were prepared with improved film and fiber forming properties. More recently, attempts have been made to synthesize polyanhydrides with greater thermal and hydrolytic stability and sustained drug release properties.
U.S. Pat. Nos. 4,757,128 and 4,997,904 disclose the preparation of polyanhydrides with improved sustained drug release properties from pure, isolated prepolymers of diacids and acetic acid. However, these biocompatible and biodegradable aromatic polyanhydrides have radical or aliphatic bonds resulting in compounds with slow degradation times as well as relatively insoluble degradation products unless incorporated into a copolymer containing a more hydrophilic monomer, such as sebacic acid. The aromatic polyanhydrides disclosed in the ""128 Patent and the ""904 Patent are also insoluble in most organic solvents. A bioerodible controlled release device produced as a homogenous polymeric matrix from polyanhydrides with aliphatic bonds having weight average molecular weights greater than 20,000 and an intrinsic velocity greater than 0.3 dL/g and a biologically active substance is also described in U.S. Pat. No. 4,888,176. Another bioerodible matrix material for controlled delivery of bioactive compounds comprising polyanhydride polymers with a uniform distribution of aliphatic and aromatic residues is disclosed in U.S. Pat. No. 4,857,311.
Biocompatible and biodegradable aromatic polyanhydrides prepared from para-substituted bis-aromatic dicarboxylic acids for use in wound closure devices are disclosed in U.S. Pat. No. 5,264,540. However, these compounds exhibit high melt and glass transition temperatures and decreased solubility, thus making them difficult to process. The disclosed polyanhydrides also comprise radical or aliphatic bonds which can not be hydrolyzed by water.
Polyanhydride polymeric matrices have also been described for use in orthopedic and dental applications. For example, U.S. Pat. No. 4,886,870 discloses a bioerodible article useful for prosthesis and implantation which comprises a biocompatible, hydrophobic polyanhydride matrix. U.S. Pat. No. 5,902,599 also discloses biodegradable polymer networks for use in a variety of dental and orthopedic applications which are formed by polymerizing anhydride prepolymers.
Biocompatible and biodegradable polyanhydrides have now been developed with improved degradation, processing and solubility properties, as well as utilities based upon their degradation products.
An object of the present invention is to provide biocompatible and biodegradable polyanhydrides which degrade into biologically active products. In one embodiment, aromatic polyanhydrides which degrade into biologically active salicylates are prepared from ortho-substituted bis-aromatic carboxylic acid anhydrides. Ortho substitution disrupts the crystallinity of the resulting polymer, enhancing solubility and processability, as well as degradation properties. The use of hydrolyzable bonds such as esters, amides, urethanes, carbamates and carbonates as opposed to radical or aliphatic bonds in these compounds further enhances these properties. In this embodiment, the polyanhydride comprises a repeating unit within the structure of Formula I: 
wherein Ar is a substituted or unsubstituted aromatic ring and R is a difunctional organic moiety substituted on each Ar ortho to the anhydride group. Ar and R are preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling biologically active materials, particularly salicylates such as aspirin, non-steroidal anti-inflammatory naphthyl or phenyl propionates such as ibuprofen, ketoprofen, naproxen, and the like, or other aromatic anti-inflammatory compounds such as indomethacin, indoprofen, and the like. Ar is preferably a phenyl group and R is preferably xe2x80x94Z1xe2x80x94R1xe2x80x94Z1-in which R1, is a difunctional moiety and both Z1s are independently either an ester, amide, anhydride, carbonate, urethane or sulfide groups. R1 is preferably an alkylene group containing from 1 to carbon atoms, or a group with 2-20 carbon atoms having a structure selected from (xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)m, (CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)m and (xe2x80x94CH2xe2x80x94CHCH3xe2x80x94Oxe2x80x94)m.
Ortho-substituted bis-aromatic carboxylic acid anhydrides are used in the preparation of the aromatic polyanhydrides of the present invention. The ortho-substituted bis-aromatic carboxylic acid anhydrides have the structure of Formula II: 
wherein Ar and R, and the preferred species thereof, are the same as described above with respect to Formula I and R is substituted on each Ar ortho to the anhydride group.
In another embodiment, polyanhydrides which degrade into biologically active alpha-hydroxy acids are prepared from bis-carboxylic acid anhydrides. In this embodiment, the polyanhydride comprises a repeating unit within the structure of Formula III: 
wherein, R is preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling an alpha-hydroxy acid. In this embodiment, R is preferably an alkylene group containing from 1 to 20 carbon atoms, xe2x80x94(CH2)xxe2x80x94 wherein x is from 1 to 20, or 
wherein x is from 1 to and Z1 and Z2 are OH so that the R group contains from 1 to 40 hydroxyl groups.
The present invention relates to compositions and methods of using compositions comprising polyanhydrides of Formula (I) or (III) in applications wherein delivery of a salicylate or an alpha-hydroxy acid to a host is desired. By xe2x80x9chostxe2x80x9d it is meant to include both animals and plants.
A more complete appreciation of the invention and other intended advantages can be readily obtained by reference to the following detailed description of the preferred embodiments and claims, which disclose the principles of the invention and the best modes which are presently contemplated for carrying them out.
Polyanhydrides which degrade into useful biologically active products such as salicylates and alpha-hydroxy acids have now been developed. Compounds comprising these polyanhydrides are useful in a variety of applications wherein delivery of a salicylate or alpha-hydroxy acid is desired.
In one embodiment, the polyanhydride comprises repeating units with the structure of Formula I: 
wherein Ar is a substituted or unsubstituted aromatic ring and R is a difunctional organic moiety substituted on each Ar ortho to the anhydride group. In this embodiment, Ar and R are preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling biologically active materials, particularly salicylates such as aspirin, nonsteroidal anti-inflammatory naphthyl or phenyl propionates such as ibuprofen, ketoprofen, naproxen, and the like, or other aromatic anti-inflammatory compounds such as indomethacin, indoprofen, and the like. Examples of the biologically active salicylates include, but are not limited to, thymotic acid, 4,4-sulfinyldinailine, 4-sulfanilamidosalicylic acid, sulfanilic acid, sulfanilylbenzylamine, sulfaloxic acid, succisulfone, salicylsulfuric acid, salsallate, salicylic alcohol, orthocaine, mesalamine, gentisic acid, enfenamic acid, cresotic acid, aminosalicylic acid, aminophenylacetic acid, acetylsalicylic acid, and the like. The identification of Ar and R moieties that provide aromatic polyanhydrides that hydrolyze to form such biologically active salicylates can be readily determined by those of ordinary skill in the art without undue experimentation. In particular, Ar is preferably a phenyl group and R is preferably xe2x80x94Z1xe2x80x94R1xe2x80x94Z1xe2x80x94 in which R1, is a difunctional moiety and both Z1s are independently either an ester, amide, anhydride, carbonate, urethane or sulfide groups. R1 is preferably an alkylene group containing from 1 to carbon atoms, or a group with 2-carbon atoms having a structure selected from (xe2x80x94CH2xe2x80x94CH2-xe2x80x94Oxe2x80x94)m, (CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)m and (xe2x80x94CH2xe2x80x94CHCH3xe2x80x94Oxe2x80x94)m or R1 may have the structure xe2x80x94R2xe2x80x94Z2xe2x80x94R3-1 wherein R2 and R3 are independently alkylene groups containing from 1 to 19 carbon atoms or groups having from 2 to 18 carbon atoms having a structure selected from (xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)m, (xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)m, and (xe2x80x94CH2xe2x80x94CHCH3xe2x80x94Oxe2x80x94)m, and Z2 is selected from the difunctional moieties described above with respect to Z1.
Ar may be an alkylaryl group, in which a difunctional organic moiety is positioned between each anhydride carbonyl group and the corresponding aromatic ring. Preferably, however, each carbonyl group is directly substituted on the corresponding aromatic ring.
Preferred polymers of this embodiment have repeating units with the structure of Formula I in which Ar is a phenyl ring and R is selected from xe2x80x94Z1xe2x80x94(xe2x80x94CH2xe2x80x94)nxe2x80x94Z1xe2x80x94, xe2x80x94Z1(xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)mxe2x80x94Z1xe2x80x94, xe2x80x94Z1(xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x80x94O2xe2x80x94)mxe2x80x94Z1-1, and xe2x80x94Z(xe2x80x94CH2xe2x80x94CHCH2xe2x80x94Oxe2x80x94)mxe2x80x94Z1xe2x80x94, wherein Z1 is an ester or amide group and n is from 1 to inclusive, and preferably is 6, and m is selected so that R has from 2 to 20, and preferably 6, carbon atoms.
The aromatic polyanhydrides of this embodiment of the present invention may be prepared by the method described in Conix, Macromol. Synth., 2, 95-99 (1996), in which dicarboxylic acids are acetylated in an excess of acetic anhydride at reflux temperatures followed by melt condensation of the resulting carboxylic acid anhydride at 180xc2x0 C. for 2-3 hours. The resulting polymers are isolated by precipitation into diethylether from methylene chloride. The described process is essentially the conventional method for polymerizing bisaromatic dicarboxylic acid anhydrides into aromatic polyanhydrides.
Aromatic polyanhydrides in accordance with this embodiment of the present invention have average molecular weights of at least about 1500 daltons, up to about 100,000 daltons, calculated by Gel Permeation Chromatography (GPC) relative to narrow molecular weight polystyrene standards.
These aromatic polyanhydrides are produced from ortho-substituted bis-aromatic carboxylic acid anhydrides having the structure of Formula II: 
in which Ar, R and the preferred species thereof are the same as described above with respect to Formula I. As noted above, ortho-substituted bis-aromatic carboxylic acid anhydrides are prepared by acetylation of the corresponding ortho-substituted bis-aromatic carboxylic acids in an excess of acetic anhydride at ref lux temperatures. The dicarboxylic acids have the structure of Formula IV, 
wherein Ar, R and the preferred species thereof are the same as described above with respect to Formula I.
The dicarboxylic acids are prepared by reacting a stoichiometric ratio of aromatic carboxylic acid having the structure Z3xe2x80x94Arxe2x80x94COOH and a compound having a structure Z4xe2x80x94Rxe2x80x94Z4 wherein Ar is a substituted or unsubstituted aromatic ring on which Z3 is substituted ortho to the carboxylic acid group, R is a difunctional organic moiety and Z3 and Z4 are functional groups selected to provide the linkage desired between the difunctional organic moiety and the two aromatic rings.
Suitable Z3 and Z4 functional groups, and the manner in which they may be reacted to produce the bis-aromatic dicarboxylic acids of the present invention, may be readily determined by those of ordinary skill in the art without undue experimentation. For example, for aromatic polyanhydrides having the structure of Formula I in which Ar is a phenyl group and R is xe2x80x94Oxe2x80x94(CH2xe2x80x94)6xe2x80x94Oxe2x80x94, the ortho-substituted bisaromatic dicarboxylic acid starting material may be prepared by reacting o-salicylic acid with 1,6-dibromohexane.
In another embodiment, the polyanhydrides degrade into biologically active alpha-hydroxy acids and comprise a repeating unit within the structure of Formula III: 
In this embodiment, R is preferably selected so that the hydrolysis products of the polyanhydrides have a chemical structure resembling an alpha-hydroxy acids. In this embodiment, R is preferably an alkylene group containing from 1 to 20 carbon atoms, xe2x80x94(CH2)xxe2x80x94 wherein x is from 1 to 20, or 
wherein x is from 1 to 20 and Z1 and Z2 are OH so that the R group contains from 1 to 40 hydroxyl groups. Examples of biologically active alpha-hydroxy acids include, but are not limited to, citric acid and malic acid. These polyanhydrides are prepared in the same fashion as described for aromatic polyanhydrides.
Polyanhydrides used in the present invention can be isolated by known methods commonly employed in the field of synthetic polymers to produce a variety of useful products with valuable physical and chemical properties. The new polymers can be readily processed into pastes or solvent cast to yield films, coatings, microspheres and fibers with different geometric shapes for design of various medical implants, and may also be processed by compression molding and extrusion. Medical implant applications include the use of aromatic polyanhydrides to form shaped articles such as vascular grafts and stents, bone plates, sutures, implantable sensors, implantable drug delivery devices, stents for tissue regeneration, and other articles that decompose harmlessly within a known time period. Polyanhydrides of the present invention can also be incorporated into oral formulations and into products such as skin moisturizers, cleansers, pads, lasters, lotions, creams, gels, ointments, solutions, shampoos, tanning products and lipsticks for topical application.
The quantity of aromatic polyanhydride that hydrolyzes to form an amount of biologically active salicylate or alpha-hydroxy acid effective for the selected use can be readily determined by those of ordinary skill in the art without undue experimentation. The quantity essentially corresponds stoichiometrically to the amount of salicylate or alpha-hydroxy acid known to produce an effective treatment for the selected use.
The present invention relates to methods of using compositions comprising these polyanhydrides in any application wherein delivery of a salicylate or alpha-hydroxy acid is desired. For example, salicylates such as salicylic acid are used routinely to treat many skin disorders including, but not limited to, acne, dandruff, psoriasis, seborrheic dermatitis of the skin and scalp, calluses, corns, common warts and plantar warts. Salicylic acid is also topically applied as an antiseptic for wounds, ulcers, and skin abscesses as it is known to exert powerful static effects against Gram-negative and Gram-positive bacteria, yeasts, dermatophytes, molds and other microbes. These antifungal properties also render salicylic acid useful in the treatment of athlete""s foot. Accordingly, topical application of a composition comprising an aromatic polyanhydride of the present invention which degrades to a biologically active salicylate is expected to be useful in the treatment of all of these conditions and/or injuries.
The anti-bacterial activity of salicylic acid also renders these polyanhydrides useful in agricultural applications. Solutions comprising a polyanhydride of Formula (I) can be applied topically to plants to establish microbial resistance against a wide range of pathogens. Salicylic acid treatment has also been shown to induce thermotolerance in mustard seedlings. Accordingly, topical application of polyanhydrides of Formula (I) is also expected to induce thermotolerance in plants.
Salicylic acid has also been shown to have anti-cataract activity in patients suffering from galactosemic cataracts. Accordingly, a solution comprising an aromatic polyanhydride of Formula (I) can also be topically applied to the eye to inhibit cataract formation.
Salicylic acid is also a powerful anti-oxidant, neutralizing highly reactive, cell damaging molecules called free radicals. In fact, salicylic acid is often the standard by which the effectiveness of other anti-oxidants is measured. Anti-oxidants are administered orally and/or topically as antiviral agents. Anti-oxidants also inhibit UV-induced signal transduction and can be used as chemopreventative agents for skin cancer. In addition, the anti-oxidant properties of salicylates have been associated with anti-aging properties, protection against ischemia and reperfusion injury, and lowering of cholesterol levels and inhibition of clotting of blood. It is believed that compositions comprising an aromatic polyanhydride of Formula (I) will also exhibit these antioxidant properties. Thus, compositions comprising an aromatic polyanhydride of Formula (I) can also be used as antiviral agents, chemopreventative agents for skin cancer, anti-aging agents, and anti-clotting agents, and to provide protection against ischemia and reperfusion injury.
Compositions of the present invention comprising a polyanhydride of Formula (III) which degrades to an alpha-hydroxy acid can be incorporated into various topical formulations and applied to the skin to promote smoother, clearer skin with less wrinkles. It is generally accepted that regular use of alpha-hydroxy acids improves the appearance of the skin by minimizing fine lines, softening dry, rough skin patches and fading age spots. Alpha-hydroxy acids are effective exfoliators which dissolve the links that bind surface skin cells together causing dead cells to slough off. This process reveals the more youthful looking skin underneath which has more even skin tone, retains moisture and is less likely to form wrinkles. Topical application of a composition comprising a polyanhydride of Formula (III) provides an effective means for delivering alpha-hydroxy acids to the skin to promote smoother, clearer skin with less wrinkles.
The following non-limiting examples set forth hereinbelow illustrate certain aspects of the invention. All parts and percentages are by weight unless otherwise noted and all temperatures are in degrees Celsius. Except for acetic anhydride and ethyl ether (Fisher Scientific), all solvents and reagents were obtained from Aldrich Chemical. All solvents were HPLC grade. All other reagents were of analytical grade and were purified by distillation or recrystallization.
All compounds were characterized by a proton nuclear magnetic resonance (NMR) spectroscopy, infrared (IR) spectroscopy, gel permeation chromatography (GPC), high performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), and thermal gravimetric analysis (TGA). Infrared spectroscopy was performed on an ATI Mattson Genesis (M100) FTIR Spectrophotometer. Samples were prepared by solvent casting on NaCl plates. 1H and 13C NMR spectroscopy was obtained on a Varian 200 MHZ or Varian 400 MHZ spectrometer in solutions of CDCl3 or DMSO-d6 with solvent as the internal reference.
GPC was performed on a Perkin-Elmer Advanced LC Sample Processor (ISS 200) with PE Series 200 LC Pump and a PE Series LC Refractive Index Detector to determine molecular weight and polydispersity. The data analysis was carried out using Turbochrom 4 software on a DEC Celebris 466 computer. Samples were dissolved in tetrahydrofuran and eluted through a mixed bed column (PE PL gel, 5 xcexcm mixed bed) at a flow rate of 0.5 mL/minute. Samples (about 5 mg/mL) were dissolved into the tetrahydrofuran and filtered using 0.5 xcexcm PTFE syringe filters prior to column injection. Molecular weights were determined relative to narrow molecular weight polystyrene standards (Polysciences, Inc.).
Thermal analysis was performed on a Perkin-Elmer system consisting of a TGA 7 thermal gravimetric analyzer equipped with PE AD-4 autobalance and Pyris 1 DSC analyzer. Pyris software was used to carry out data analysis on a DEC Venturis 5100 computer. For DSC, an average sample weight of 5-10 mg was heated at 10xc2x0 C./minute at a psi flow of N2. For TGA, an average sample weight of mg was heated at 20xc2x0 C./minute under a 8 psi flow of N2. Sessile drop contact angle measurements were obtained with an NRL Goniometer (Rame-hart) using distilled water. Solutions of polymer in methylene chloride (10% wt/volume) were spun-coated onto glass slips, at 5,000 rpm for seconds.